Project Summary/Abstract This project addresses a critical gap in the understanding of sexual dimorphism in both infant and children?s health outcomes, where males are often at increased risk for disease. At the project?s core is the novel hypothesis that sexual epigenetic dimorphism in the placenta influence responses to perinatal stressors, and predict fetal growth restriction and neurodevelopment ND later in life. To address this, we use an ?-omics? and systems-wide approach to identify biomarkers of, and potential mechanisms for, adverse pregnancy outcomes (fetal growth restriction and neurodevelopmental impairment in the offspring) in an existing cohort of children born extremely prematurely (i.e., before 28 weeks of gestation). The ?omics approaches include DNA CpG methylomics, transcriptomics to assess messenger RNA), and proteomics. A tremendous strength of this proposal is the unique and extensively characterized US-based cohort recruited for the Extremely Low Gestation Age Newborn (ELGAN) Study. Since its initiation in 2001, the broad goal of the ELGAN Study has been to evaluate the relationship between perinatal inflammation and neurodevelopmental impairments among individuals born extremely premature. In the proposed project, we build on the success of the ELGAN Study by: 1) evaluating ?-omics? biomarkers in archived specimens of placenta and neonatal blood and 2) integrating these data with existing outcome data about fetal growth restriction and neurodevelopmental impairments in the ELGAN cohort. In the first three years of the project, DNA CpG methylation, mRNA, and selected proteins will be assayed in archived specimens of placenta and neonatal blood. Data analyses will begin in year 2, with an initial focus on establishing the relationships among placental and blood biomarkers and both fetal growth restriction as well as neurodevelopmental impairment. We also will study relationships between prenatal factors associated with adverse pregnancy outcomes (maternal obesity and placental bacteria) and placental and neonatal blood ?omics biomarkers. Furthermore, we will evaluate relationships between will placenta biomarkers and neonatal blood biomarkers. Innovative aspects of this project include its longitudinal perspective, consideration of placenta epigenetics as a mechanism linking prenatal exposures to childhood outcomes, and evaluation of CpG methylation marks in neonatal blood. With the potential for public health impact, this research may inform the development of therapies targeting epigenetic processes to prevent or ameliorate cognitive disability, thereby improving the quality of life for 16,000 individuals who survive extremely premature birth each year in the United States.